Integrin/ligand interaction is involved in the pathogenesis of many diseases and, therefore, is a therapeutic target. Significant findings in the field of integrin studies have been recently published, including: 1) The crystal structure of the I domain; 2) A Beta-propeller model of the alpha subunit N-terminus; 3) An I-domain-like structure in the Beta subunit; and 4) A model of integrin activation. Our discoveries during the current project period include: 1) Ligand binding sites in the I domain; 2) Residues in the proposed Beta-propeller domain that are critical for ligand binding; 3) Residues that determine ligand specificity in Beta subunits; and 4) multiple conformation-dependent epitopes in the Beta subunit. These findings complement the crystal structure of the alpha I domain, and substantiate the proposed models. Based on progress during the current project period, we propose to study: 1) the role of the proposed Beta-propeller domain in I domain/ligand interaction; 2) the role of the diverse region in the Beta2 subunit that determines ligand specificity; 3) the binding sites in Beta2 integrins for ligand-derived binding motifs in I-domain integrins; and 4) the role of cation binding in I domain/ligand interaction. The proposed studies will lead to an increase in our understanding of integrin structure, regulation, and ligand interactions. These studies could potentially lead to the design of inhibitors or activators that could be useful for preventing cancer metastasis, rejection of a transplanted organ, or other medical conditions.